Adaptive immune responses are initiated by the presentation of antigenic peptides to naive T cells. Antigen presentation occurs in the context of innate responses induced by pathogens. IL-12 is produced by phagocytes in response to many microorganisms and its presence during antigen presentation directs responding T cells to develop into Th1 cells, the appropriate effector cells for eliminating intracellular pathogens. Recently, evidence has accumulated that dendritic cells are especially equipped to initiate immune responses, including Th1 responses. However, macrophages also present antigens after infection and their role in influencing the development of the adaptive response must not be overlooked. We have focused upon the initiation of a Th1 response to the protozoan parasite, Leishmania major. Leishmania species are a significant cause of infectious disease in many tropical countries. Experimental infection of mice with L. major is a well-characterized and highly reproducible model of leishmaniasis. IL-12 is produced after infection with L. major and is necessary for the development of an appropriate Th1 response, but the source of IL-12 during L. major infection is unknown. While investigating the presentation of L. major antigens to naive transgenic T cells, we discovered that naive T cells can induce macrophages to secrete IL-12. Interestingly, the antigen dose required for T cell induction of IL-12 was lower than that required for stimulation of the T cells. We propose to investigate this potential source of IL-12 further. Our primary hypothesis is that the ability of naive T cells to induce IL-12 at low antigen doses is unique to macrophages. The first two specific aims address this hypothesis by (1) testing whether another model transgenic T cell is capable of inducing IL-12 from macrophages during antigen presentation; and by (2) testing whether dendritic cells can be induced by naive T cells to produce IL-12 at nonstimulatory doses of antigen. In the third specific aim we address the mechanism by which naive T cells induce IL-12, specifically whether CD40-CD40L interactions are necessary. Finally, we propose experiments which may identify innate cofactors that modulate this ability of naive T cells to induce IL-12. Because macrophages may be the first phagocytes to present antigens to T cells, this interaction may reinforce innate responses to infection and influence the course of the developing adaptive response.